Mucociliary Clearance System
Mucous secretions are normally removed via the mucociliary clearance (MCC) system, which relies on the integrated action of mucus secretion by goblet cells and submucosal glands; the movement of cilia on epithelial cells which propels the mucus across the luminal surface; and ion transport into and out of luminal epithelial cells which controls the flow of water into the mucus.
The most common diseases associated with a disorder of mucous hydration, secretion and clearance are diseases of the airways, resulting from retained mucus secretions such as chronic obstructive pulmonary disease, chronic bronchitis, cystic fibrosis, primary ciliary dyskinesia, sinusitis and otitis media, and pneumonia.
Disorders of mucus secretion may also cause improper hydration at other sites of the body, thereby resulting in pathological conditions, such as dry eye disease, nasolacrimal duct obstruction, retinal detachment, glaucoma or ocular hypertension, retinal degeneration, vaginal dryness, gastroesophageal reflux, dry mouth, and constipation.
Enhancement of mucociliary clearance or balanced tissue hydration would thus be useful in the prevention, management and treatment of such disorders. Furthermore, enhancement of mucociliary clearance would also have diagnostic applications such as sputum induction and detection of lung cancer.
P2Y-R Ligands as Potential Drugs for MCC System Disorders
The P2-receptor superfamily, consisting of ligand-gated ion-channels (P2X-Rs) and G-protein coupled receptors (P2Y-Rs), are activated principally by ATP (and by ADP or UTP at several receptor subtypes). P2Y-Rs are attractive pharmaceutical targets due to their involvement in the modulation of many tissues and organs under both normal and pathophysiological conditions, thus making P2Y-R agonist potential drugs. P2Y purinergic receptor agonists are known as modulators of all components of the MCC system. They increase both the rate and total amount of mucin secretion by goblet cells in vitro, increase cilia beat frequency in human airway epithelial cells in vitro, increase Cl− secretion and, hence, water secretion from airway epithelial cells in vitro, and release surfactant from Type II alveolar cells. In addition to such actions, P2Y agonists also regulate phospholipase C through an extracellular 5′-nucleotide receptor in human airway epithelial cells.
Several U.S. patents disclose dinucleoside polyphosphates said to be highly selective P2Y purinergic receptors agonists and useful in the prevention, management or treatment of diseases and disorders associated with abnormalities of tissue fluid secretion, hydration and clearance, including chronic obstructive pulmonary diseases (chronic bronchitis, primary ciliary dyskinesia, cystic fibrosis, immobility-associated pneumonia), sinusitis, otitis media, nasolacrimal duct obstruction, dry eye disease, glaucoma, retinal degeneration and edematous retinal disorders including retinal detachment, vaginal dryness, and gastrointestinal tract disease (e.g. U.S. Pat. Nos. 6,555,675, 6,867,199, 5,837,861, 6,348,589, 6,420,347, 6,673,779, 5,789,391, 5,763,447, 6,703,376, 5,968,913, 6,331,529, 6,436,910, 6,323,187, 6,143,279, 6,022,527, 6,159,952, 6,423,694, 6,596,725, 6,818,629, 5,900,407, 6,696,425, 6,864,243, 6,624,150 and 6,462,028).
Pathophysiology of Diabetes Mellitus
Diabetes mellitus is one of the most prevalent chronic diseases in the Western world, affecting up to 5% of the population. It is a heterogenous group of disorders characterized by a chronic hyperglycemia—results from defects in insulin secretion, insulin action, or a combination of both—with additional abnormalities in lipid and protein metabolism. In addition to its chronic metabolic abnormalities, diabetes is associated with long-term complications involving various organs, especially the eyes, nerves, blood vessels, heart and kidney, which may result in blindness, amputations, cardiovascular disease and end stage renal disease. The development of diabetic complications appears to be related to the chronic elevation of blood glucose. There is no current cure for diabetes, however, effective glycemic control can lower the incidence of diabetic complications and reduce their severity.
The two major forms of diabetes are classified as type 1 and type 2, previously termed non-insulin-dependent diabetes mellitus (NIDDM), which affect approximately 95% of patients with diabetes.
Type 2 diabetes appears to be a complex polygenic disease in which insulin resistance and relative insulin deficiency coexist. Thus, improvement of insulin secretion is a major therapeutic goal. The deficiency of insulin release expresses itself not only by the absence of first-phase insulin response to glucose, but also by a global reduction in the magnitude of insulin release to 10-20% of the normal secretory capacity (Cerasi, 1992). Patients with type 2 diabetes are treated with various oral antidiabetic agents, insulin injections, or a combination of both. The currently available oral antidiabetic drugs are targeted at either reducing peripheral insulin resistance, increasing insulin secretion from the pancreatic beta-cell, or slowing the absorption of carbohydrates from the intestine.
Approximately half of the patients with type 2 diabetes are treated with oral agents, a considerable proportion of them with agents that stimulate insulin secretion. The choice of insulin secretagogues is limited to the sulfonylureas and related compounds (“glinides”), which elicit insulin secretion by binding to a regulatory subunit of membrane ATP-sensitive potassium channel, inducing its closure (Lebovitz, 1994). Nevertheless, sulfonylureas have several undesired effects in addition to possible long-term adverse effect on their specific target, the pancreatic beta-cell. These side-effects include the risk of hypoglycemia due to stimulation of insulin secretion at low glucose concentrations, the difficulty of achieving normal glycemia in a significant number of patients, the annually 5-10% secondary failure rate of adequate glycemic control, and possible negative effects on the cardiovascular system (Lebovitz, 1994; Leibowitz and Cerasi, 1996; Brady and Terzic, 1998). Two types of agents are used to attenuate peripheral insulin resistance: the biguanide metformin and the thiazolidinedione analogues (Edelman, 1998). The α-glucosidase inhibitor, pseudotetrasaccharide acarbose, is used to slow intestinal absorption of carbohydrates.
P2Y-R Ligands as Potential Antidiabetic Drugs
The presence of P2Y-Rs on pancreatic beta cells is well documented (Loubatières-Mariani et al., 1979; Chapal and Loubatières-Mariani, 1981; Bertrand et al., 1987; Bertrand et al., 1991) and their activation results in stimulation of insulin secretion at stimulating glucose concentrations. The mechanism whereby P2Y-R agonists enhance glucose-induced insulin release may involve the cyclic AMP/Protein Kinase A signaling pathway (Petit et al., 2000), which has been reported to increase the effectiveness of the K+ATP channel-independent action of glucose (Yajima et al., 1999).
Various P2-R selective ligands have been shown to increase insulin secretion and decrease glycemia in vivo (Ribes et al., 1988; Hillaire-Buys et al., 1993). The list of ligands include 2-methylthio-ATP, which breaks down rapidly into adenosine thus was injected directly to the pancreatico-duodenal artery (Ribes et al., 1988), and adenosine 5′-O-(2-thio)diphosphate, which is stable to enzymatic hydrolysis thus was administered either intravenously or orally (Hillaire-Buys et al., 1993).
Almost all current synthetic P2-receptor agonists are modifications of the ATP or UTP pharmacophore. The purine (pyrimidine) ring system, the ribose moiety, or the triphosphate chain are modified at one or more positions (Fischer, 1999). Previously, we have reported the synthesis of ATP derivatives bearing a long thioether substitution at C-2 position, such as 2-thioether-5′-O-(1-thiotriphosphate) adenosine derivatives (Fischer et al., 1999). WO 03/034978 of the same applicant discloses 2-substituted-5′-O-(1-boranotriphosphate)-adenosine derivatives that act through P2Y(ATP/UTP)-receptors, present in the membrane of pancreatic beta cells, as insulin secretagogues with high efficacy and potency, enhancing insulin secretion at the nM concentration range, under slightly stimulatory glucose concentration.